Targeted mRNA therapies treating ARDS

治疗 ARDS 的靶向 mRNA 疗法

• 批准号: 10740571
• 负责人: Zhengjie Zhou
• 金额: $ 11.06万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740571
• 关键词: 2019-nCoV; Acute Lung Injury; Acute Respiratory Distress Syndrome; Advisory Committees; Alveolar; Antiviral Agents; Antiviral Response; Automobile Driving; Bacteria; Binding; Blood Vessels; COVID-19; COVID-19 mortality; COVID-19 patient; Cause of Death; Cell Adhesion; Cell Line; Cells; Chicago; Community Medicine; Critical Illness; Data; Development Plans; Disease; Doctor of Philosophy; Edema; Encapsulated; Endothelial Cells; Endothelium; Engineering; Epithelial Cells; Epithelium; Event; Evolution; Experimental Designs; Functional disorder; Goals; Health; Homeostasis; Human; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Innate Immune Response; Interdisciplinary Study; Interferons; Kruppel-like transcription factors; Lead; Ligase; Liposomes; Lung; Lung diseases; Lung infections; Malignant Neoplasms; Mechanical ventilation; Medicine; Mentors; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Mutation; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmacological Treatment; Play; Positioning Attribute; Postdoctoral Fellow; Proteins; Publishing; Pulmonary Edema; Pulmonary Inflammation; Pulmonary alveolar structure; Rattus; Research; Research Personnel; Ribonucleases; Role; SARS-CoV-2 infection; Scientist; Small RNA; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Tidal Volume; Tissues; Training; Universities; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Virus Replication; Water; alveolar epithelium; biosafety level 3 facility; career development; clinically relevant; cytokine release syndrome; endothelial dysfunction; in vivo; inflammatory lung disease; influenzavirus; inhibitor; innate immune pathways; innovation; lung injury; mRNA delivery; monolayer; mortality; mouse model; nanomedicine; nanoparticle; nanotherapeutic; novel; oligoadenylate; protein function; rational design; research and development; respiratory virus; response; restoration; stem; targeted delivery; therapeutic effectiveness; therapeutic evaluation; transcription factor; vaccine development; vascular endothelial dysfunction; ventilation; viral RNA; viral pandemic

Project Summary/Abstract: This proposal describes a research and career development plan for Zhengjie Zhou, Ph.D., to transit from a postdoctoral fellow to an independent investigator position. This proposal will be based on Dr. Zhou’s past years of multidisciplinary research in nanomedicine and vascular research. Dr. Zhou will be trained at the University of Chicago by a superb advisory committee of experts who are world-renowned scientists including Dr. Yun Fang (primary mentor), Dr. Matthew Tirrell (co-mentor), Dr. Jeffrey Hubbell, Dr. Gökhan Mutlu and Dr. Glenn Randall. This proposal tests the overall hypothesis of fabricated novel lung-targeting liposomal nanoparticles to deliver therapeutic mRNA in a cell-specific manner for the treatment of acute respiratory distress syndrome (ARDS), which is the major cause of death for severe influenza and SARS-CoV-2 infection. Currently, efficient medicines are still lacking for ARDS therapy. ARDS is characterized by the dysfunction of endothelial cells (ECs), epithelial cells and the following uncontrolled cytokine storm. Based on our recent research about a vascular cell adhesion molecular-1 (VCAM1) targeting nanotherapeutic study, I rationally designed and optimized a targeting liposomal nanoparticle that enables robust mRNA delivery in vivo in a cell- specific manner. Leveraging this mRNA delivery platform, We propose to (i) promote endothelium health by endothelial cell-specific delivery of KLF2 mRNA to restore KLF2, a transcription factor, that plays a key role in facilitating endothelial health and vasculature homeostasis. KLF2 was demonstrated significantly reduced in mice lungs induced by LPS, influenza H1N1, SARS-CoV-2, and COVID-19 patients lungs; (ii) activate epithelial cells innate immune pathway by epithelium-specific delivery of 2’-5’-oligoadenylate synthetase 1 (OAS1) mRNA to augment epithelium interferon (IFN) response through OAS/RNase L pathway to defense respiratory viral infection. Our data demonstrated that KLF2 mRNA/VCAM1-targeting liposome targeted the inflamed mice lungs endothelium and significantly reduced the ARDS induced by H1N1 and SARS-CoV-2. Our preliminary data demonstrated the OAS1 mRNA/epithelium-targeting liposome targeted the mice inflamed lung epithelium and significantly reduced the H1N1 replication and lung ARDS. In this project, I will comprehensively evaluate the therapeutic potency of VCAM1-targeting liposome to restore endothelial KLF2 and lessen ARDS induced by (i) H1N1, or (ii) SARS-CoV-2 in mouse models (Aim 1, K99), and in a clinically relevant rat ARDS model induced by high-tidal ventilation (HTV) (Aim 2, K99/R00). I will determine how epithelium-targeted delivery of OAS1 activates the innate immune response and exerts antiviral effects in mice by OAS1 mRNA/epithelium-targeting liposome and will determine its therapeutic effect to treat respiratory virus induced ARDS (Aim 3, R00). Successful complete these projects will provide a promising mRNA therapeutic treating lung disease and provide an “effective responder” in viral pandemics regardless of virus evolution and mutation. This mRNA delivery platform is adaptable and potentially beneficial for various diseases treatment.

项目总结/文摘: